The cellular and molecular mechanisms of free radical-related pancreatic islet cell destruction are incompletely understood. Pharmacological modulation of this islet cell death may provide novel avenues for the experimental therapy of diabetes. Recent studies in isolated islet cells, and other cell types demonstrate that peroxynitrite and hydrogen peroxide, potent oxidants produced during immune-cell mediated islet cell attack, trigger an intracellular cascade culminating in cellular energy failure. DNA strand-breakage triggered by hydrogen peroxide and peroxynitrite is recognized by a specific domain of the nuclear enzyme poly (ADP-ribose) synthetase (PARS). This results in the activation of PARS which initiates an energy consuming inefficient repair cycle, with resultant depletion of dinucleotide pools, slowing the rate of glycolysis and mitrochondrial respiration, reducing ATP synthesis. Thus, PARS acts as a terminal mediator of cellular energetic collapse leading to cellular necrosis. Our preliminary data show that pharmacological inhibition of PARS with a novel, potent inhibitor of PARS reduces the development of hyperglycemia and islet cell destruction in a rat model of streptozotocin- induced diabetes. The inhibitor was effective in the oral treatment regimen. In addition to the data with pharmacological inhibitors, data from our group, and also from two other group, and also from two other groups of investigators demonstrate that PARS deficient (knockout) mice are resistant against streptozotocin-induced diabetes. Because of the streptozotocin-model is not fully predictable for the human situation, the first aim of the current protocol is aimed at investigating the effect of oral treatment with PARS inhibitor on the development of spontaneous autoimmune diabetes (NOD mice). The second aim of the proposed studies is to perform standard preclinical studies to begin to characterize the toxicity and pharmacodynamics of orally administered PARS inhibitor. The current proposal will provide (1) novel mechanistic information on the mechanism of autoimmune diabetes, and (2) will result in data which will help our company in making a strategic decision for the preclinical development of a novel, potent, orally active PARS inhibitors. PROPOSED COMMERCIAL APPLICATION: To market for a safe and effective therapy for autoimmune diabetes is estimated at > $1 billion in the US per annum.